J. Am. Chem. SOC.1993,115, 10139-10146
10139
Conformationally Rigid Acyclic 2,2,6,6-Tetramet hyl- 3,5-Hept anediol (TMHDiol) Derivative as a New Class of Chiral Auxiliaries Ichiro Suzuki, Hirofumi Kin, and Yoshinon Yamamoto* Contribution from the Department of Chemistry, Faculty of Science, Tohoku University, Sendai 980, Japan Received June 10, 1993'
Abstract: As a new chiral auxiliary, a 2,2,6,6-tetramethyl-3,5-heptanediol (TMHDiol) derivative has been developed. This chiral auxiliary is an acyclic, but strongly conformationally biased, molecule. Conjugate addition of lithium N-benzyl-N-(trimethy1silyl)amide (LSA) to the enoates having a TMHD auxiliary proceeded with high diasteroselectivities to give @-aminoesters in high yields, although the use of conventional auxiliariessuch as 8-phenylmenthyland oxazolidone resulted in low diastereoselectivity. Organocopper conjugate addition to TMHD crotonate, heptanoate, and cinnamate produced high diastereoselectivities,and Diels-Alder reaction of TMHD acrylate with cyclopentadiene in the presence of Tic14 afforded an endo adduct exclusively with high diasteroselectivity. The addition of LSA proceeded via an s-cis conformation of enoates, but the organocopper addition in the presence of BFs.OEt2 and the Diels-Alder reaction in the presence of Tic14 proceeded through an s-trans form.
The molecular design of chiral auxiliariesis becoming a subject of keen interest in organic synthesis. In general, molecules 1 containing a chiral auxiliary consist of three units; a shielding part, a reactive part, and a tether which connects a shielding and a reactive part (Scheme I). The conformational rigidity of auxiliaries is essential to produce high asymmetric induction. For that reason, conformationallyfixed cyclic or metal-chelated rigid auxiliaries have commonly been used for asymmetric synthesis (for example, rigid template in Scheme I).I The use of acyclic molecules as the tether is not common because of their conformational unpredictability. However, an acyclic template has a potential for adopting an induced fit type conformation because of its flexibility. De Clerq et al. have used simple propane derivatives 2,having a substituent at the C-2 position, as an open chain template.2 The introduction of a sterically bulky anchor (A = trityl) afforded significant diastereomeric excess (72-76%) in the Diels-Alder reaction of 2 (Y = Ph, X = 02CCH=CH*) with cyclopentadiene.2 The gem-dialkyl effect, which is the name given to the acceleration of a cyclization due to the substitution of alkyl groups for hydrogen atoms on the carbon chain, might also bring X close to Y (3): and actually such an effect has been observed for intramolecular cyclization reactions. More recently, *Abstract published in Advance ACS Abstracts, October 1, 1993. (1) For reviews, see: (a) Yamamoto, Y.; Sasaki, N. The stereochemistry of C-C Bond Formation via Metal Enolates. In Stereochemistry of Organometallic and Inorganic Compounds Bernal, I., Ed.; Elsevier: Amsterdam, 1990 Vol. 4, p 3. (b) Morrison, J. D., Ed. Asymmetric Synthesis; Wiley: New York, 1983-1985; Vol. 1-5. For chiral auxiliaries of esters and amides, see: (c) Opplzer, W. Tetrahedron 1987,43, 1969. (d) Helmchen, G. Tetrahedron Lett. 26, 3095. (e) Whitesell, J. K.; Yaser, H. K.J. Am. Chem. Soc. 1991, 113, 3526. Whitesell, J. K.; Younathan, J. N.; Hurst, J. R.; Fox, M. A. J. Org. Chem. 1985,50, 5499. (0 Evans, D. A.; Chapman, K. T.; Hung, D. T.; Kawaguchi, A. T. Angew. Chem., In?. Ed. Engl. 1987, 26,1184. (8) Seebach, D. Angew. Chem., In?. Ed. Engl. 1988,27,1624. (h) Mukaiyama, T. Challenges in Synthetic Organic Chemistry; International Series of Monographs on Chemistry 20. Oxford Univ. Press: Oxford, 1990. (i) Rawson, D. J.; Meyers, A. I. J. Org. Chem. 1991,56, 2292. (j) Stack, J. G.; Curran, D. P.; Rebek, J., Jr.; Ballester, P. J. Am. Chem. SOC.1991,113, 59 18. (k) Tamai, Y.; Koike, S.; Ogura, A,; Miyano, S.J. Chem. SOC.,Chem. Commun. 1991,799. (1) Akiyama, T.; Nishimoto, H.; Ozaki, S.Tetrahedron Lett. 1991, 32, 1335. (2) (a) De Corte, F. A. J.; De Clerq, P. J. Bull. Soc. Chem. Belg. 1988, 97,493. (b) Missiaen, P.; De Clerq, P. J.; van Meervelt, L.; King, G. S. D. Bull. Soc. Chim. Belg.; 1988,97,993. (c) Couwberghs, S.;De Clerq, P. J.; Tinant, B.; Declerq, J. P. Tetrahedron Lett. 1988, 29, 2493. (3) For the gem-dialkyl effect, see: Jung, M. E.; Gervay, J. J . Am. Chem. Soc. 1991, 113, 224. For the Thorpe-Ingold effect, see: Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. SOC.1915, 107, 1080.
Saito and his co-workers have reported very high asymmetric induction via a strongly conformationally biased acyclic system without the assistance of ~helation.~ We report that the 1,3di-tert-butyl-substitutedpropane unit acts as a conformatinoally homogeneous template (4) without the assistance of chelation. The use of this new template enables us to achieve high asymmetric induction in the Michael additions of lithium N-benzyl-N(trimethylsily1)amide (LSA) to enoates, while the use of an 8-phenylmenthyl or an oxazolidone chiral auxiliary resulted in low diastereoselectivities. Furthermore, organocopper conjugate additions and Diels-Alder reactions of enoates bearing this template produce high diastereoselectivities.
Results and Discussion Synthesis of meso-2,2,6,6,-Tetramethyl-3,5-heptanediol (TMHDiol) (6) and Its Derivatives. We previously reported that meso-dimethylglutric hemialdehyde 5adopts a rigid conformation in solution without any assistance of chelating reagent^.^ It was though that the conformational property of 5 would be between a rigid cyclic and a flexible acyclic molecule, and thus we were interested in utilizing such a tailor-made molecule6 as a chiral auxiliary. Extension of techniques learned in the study of 5 led us to synthesize meso-2,2,6,6-tetramethyl-3,5-heptanediol (6) (TMHDiol). As shown in Scheme 11, racemic 6 (syn isomer) was prepared in high yield via aldol condensation between pinacolone and pivalaldehyde followed by reduction with Dibal? TMHDiol ( 6 ) was treated with KH and BzCl to give (*)-7, which was converted to q h n s a t u r a t e d esters 8 upon treatment with enoic acid chlorides in the presence of AgCN.8 The X-ray structural analysis of (racemic) TMHD cinnamate (Sa) is shown in Figure 1. It is clearly demonstrated that one side of the double bond, C W 7 , is shielded effectively by the phenyl group of the benzoate ester, and the enoate moiety adopts an s-cis conformation. (4) Saito, S.; Hirohara, Y.; Narahara, 0.;Moriwake, T. J. Am. Chem. Soc. 1989,111,4533. ( 5 ) Yamamoto, Y.; Nemoto, H.; Kikuchi, R., ;Komatsu, H.; Suzuki, I. J. Am. Chem. SOC.1990,112, 8598.
(6) A fuzzy molecule may change its conformation by tuning the steric and stereoelectronic effects of the substituent, although a rigid cyclic system never alters. (7) Kiyokawa, S.; Kuroda, H.; Shimansaki, Y. Tetrahedron Lert. 1986, 27, 3009. (8) Takimoto, S.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. SOC.Jpn. 1976, 49, 2335.
OOO2-7863/93/1515-10139$04.00/00 1993 American Chemical Society
10140 J. Am. Chem. SOC.,Vol. 115, No. 22, 1993
-
Suzuki et al.
Scheme I. Chiral Auxiliaries with Acyclic Tethero tether Shielding site Y Reactive site x rigid template 1
2
4
3
OAn auxiliary consists of a tether and a shielding site.
Scheme II. Synthesis of Enoates Bearing a Racemic TMHD Auxiliary
1
LBu
1) LDA. THF, -7VC
*
2)tBuCHO
UtBu
Dibal(2 equiv). THFi;78'C
mu
97%
1) KH. THF. room temp 2) PhCOCl w 99%
tBu
97%
Sa; R=Me, 86% b;R=Et, 78%
7 (racemic)
E; R=Bu,
5
9
66%
d;R=W, 85% e;
R=H, 74%
Scheme III. Synthesis of Enoates Having a Chiral TMHD Auxiliary
Lo. *
KH. a-menthoxyacetyl chloride, THF
*
6
tBuU
76%
separation by HPLC;
BOMCI. iR2NE1
t
B
U
BOMO d tBu
97%
R* = a-menthyl 10
1) KOH. MeOH. HzO 2) BzCI. py; H2. cat Pd(0Q
t Bu
89%
11
utBu HO
L O R *
OB2
a
tBu
3
~
2
a
LDA. PhSeSePh;H20z
MeA 0
2PY*~a Z 0C I 2
85%
tBuU
7 (chiral)
t
B
U
+
8a (chid)
95%
12 BOMO
0%
Br
tBu&tBu
- QBz -
HQ
t B u u t B u
Hb HC
13
7' ( c h i d )
The effective shielding of the double bond of 8a by the phenyl ring was also confirmed in solution. The 'H NMR spectrum of 8a in CDCls showed the following coupling constants and chemical shifts (see 9); Jac= Jod = 8.5 Hz, Jab = JM = 2.5 Hz, 6 He 5.55 ppm and 6 Hf 6.58 ppm, protons of R(Me) 6 1.60 ppm. The olefinic and methyl protons are significantly shielded by the aromatic ring, since the chemical shifts of Heand Hf move upfield by ca. 0.4ppm in comparison with the chemical shift of ordinary olefinic protons. It is clear that 8 is a conformationally rigid acyclic molecule. The synthesis of enantiomers of 7 and Sa is shown in Scheme 111. TMHDiol(6) was converted to a mixture of diastereomers of 10 upon treatment with a-menthoxyacetyl chloride, which was separated by HPLC. Treatment of one of the diastereomers with (benzy1oxy)methyl chloride (BOMCI) gave 11. Removal of the a-menthoxyacetyl group upon treatment with KOH, benzoyl protection of the free alcohol, and removal of the BOM
acrylic acid Zchloro-1-methylpyridinium iodide. U3 N. CH2CI2. reflux
w
dQ
- QBZ -
t B u u t B u
74%
14 ( c h i d )
group produced chiral 7 in good yield; [a]23D30.27' (c 0.094, C6H6). An enantiomer 7' was prepared similarly from the other diastereomer of 10; [cY]~~D -30.42O (c = 0.093,C6H6). The absolute configuration of chiral7 was determined unambiguously by X-ray analysis of the bromophenyl derivative 13, which was prepared from 11 using p-bromobenzoyl chloride instead of benzoyl chloride (Figure 2). Now both enantiomers were in hand. However, the reaction of crotonyl chloride with chiral 7 in the presence of AgCN resulted in racemization. The racemization presumably took place in the following way: the AgCN method produced HCN, which equilibrated the benzoyl group via migration between the two oxygens of chiral 7. Accordingly, esterification under acidic conditions should be avoided. We chose a two-step synthesis for this particular case. Treatment of chiral7 with butyryl chloride in pyridine-CHzClz gave 12without racemization in 85% yield. The phenylselenylation of 12 using LDA-PhSeSePh followed by deselenylationwith HzOz produced
J. Am. Chem. SOC., Vol. 115, No. 22, 1993 10141
2.2,6,6-Tetramethyl-3.5-heptanediol Derivative
Conjugate Addition of LSA to 8 (Racemic)"
Table I.
entry
2
1 2 3 4
8(R)
solvent
yield, % diastereomer ratio (recovery of 8) 17:18
8a(Me) T H F
95 67 (21) 75 (20) 30(49)
8b(Et) THF 8d(Ph) T H F 8d(Ph) THF-l3%HMPA
95:5 95:5 933 92:8
" The reaction of LSA (0.42 mmol) with 8 (0.41 "01) was carried out at -78 OC. The diastereomer ratio was determined by 'H N M R spectra. addition of metal amides to enoates is needed for chiral synthesis of B-lactam antibiotics.lkJ1 Accordingly, we examined the conjugate addition of LSA to the enoates 15 and 16 having conventional auxiliaries. The addition of LSA to both enoates proceeded regioselectively in a 1,Cmanner to give the corresponding @-aminoesters in high yields, but the diastereoselectivities were not high: 70% de was obtained from 1512 and 40% de from 16. Then, the conjugate addition of LSA to racemic TMHD enoates (8a,b,d) was studied, and the results are summarized in Table I. Very high diastereoselectivity was
Heu
Figure 1. ORTEP diagram for 8d.
.
l
:
h
LSA iLIN(SIMq)CH,Ph
P
15; Y*=8-phenylmenthyloxy 16; Y *E (4S)4(1-methylethyl)-2-oxalidinone BnNH
0
18 a; R=Me b; R = B E; R=Ph
17 a; R=Me b,R=Et e; R=Ph
BnC-H
Figure 2. ORTEP diagram for 13.
1 ) LSAITHF. -78°C
Sa (chiral)
chiral 8a in 95% yield. The RCOC1-pyridine method for the esterification of 7 was not applicable to crotonyl chloride bearing allylic hydrogens, presumably because the y-hydrogen would be abstracted by the base; in fact, cinnamoyl chloride having no allylic hydrogens was able to be used as RCOCl and its direct esterification was accomplished. The acrylate derivative 14 was synthesized by the esterification of 7' (chiral) with acrylic acid using 2-chloro-1-methylpyridinium iodideEtsN.9 The optical purity of chiral8a and 14 was checked by examination of their 1H NMR spectra in the presence of Eu(hfc)z, which established that no racemization took place during the esterification steps. Conjugate Addition of Lithium N-Benzyl-N-(trimethylsilyl)amide (ISA). Recently, we have reported that LSA is an excellent nucleophile which adds only in a 1,Cmanner to enoates such as crotonateswithout being accompaniedby 1,Zaddition or hydrogen abstraction at the y-position.10 The resulting j3-amino esters" are important for the synthesis of biologically active natural products, including Blactams. Especially,asymmetricconjugate (9) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045. (10) (a) Uyehara, T.; Asao, N.; Yamamoto, Y. J. Chem. SOC.,Chem. Commun. 1987, 1410. Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1988, 44, 4173. (b) Uyehara, T.; Asao, N.; Yamaoto, Y. J. Chem. Soc., Chem. Commun. 1989, 753. Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1990, 46, 4562. (c) Uyehara, T.; Shida, N.; Yamamoto, Y . J. Org. Chem. 1992, 57, 3140. (d) Shida, N.; Uyehara, T.; Yamamoto, Y . J. Org. Chem. 1992,57,5049. (e) For asymmetric conjugate addition of amide cuprates to enoates bearing chiral auxiliaries, see: Yamamoto, Y.;Asao, N.; Uyehara, T. J. Am. Chem. Soc. 1992, 114, 5427. ( 1 1) (a) D'Angelo, J.; Maddaluno, J. J. Am. Chem. SOC.1986,208,8112. (b) Matsunaga, H.; Sakamaki, T.;Nagaoka, H.; Yamada, Y. Tetrahedron Lett. 1983, 24, 3009. (c) Daviea, S. G.; Ichhihara, 0. Tetrahedron: Assymmetry 1991, 2, 183. (12) The amide cuprate reagent of LSA gave 72% de upon treatment with 15 (see ref 10e). (13) Estermann, H.; Seebach, D. Helv. Chim. Acta 1988, 71, 1824.
2)LiAIH4Et20
-
w
19
-OH
[a]270 59.4' (c 0.092, &OH)
89% ee
+" 20. s s i s
21
obtained in all cases (entries 1 4 ) . As expected from the X-ray structural analysis of 8d and from the 'H NMR spectrum of 8e, the aromatic ring blocks the back face of the double bond when in the s-cis conformation (see 9), and therefore the nucleophile is forced to attack from the front side. In order to confirm this mechanism and determine the stereochemistry of 17 (the major product), the conjugate addition of LSA to chiral8a was carried out. The resulting @-aminoesters were converted to aminoalcohol 19upon treatment with LiAlH4: [aI2'D + 59.4' (~0.092,EtOH). The absoluteconfiguration (S)of 19was determined by comparing its [al~value with that of authentic (3S)-3-(benzylamino)butanol, CY]^) 31.5' (c 1.8, CHC13), for ca. 45% ee.13 It is known that the conjugate addition of LSA to methyl crotonate proceeds via the s-cis conformation.lob The observed results imply that the addition proceeds through a six-membered transition state 20 in which lithium coordinates to the oxygen of the enoate carbonyl group, in accord with the previous X-ray and spectral data supporting an s-cis conformation. When HMPA was added to THF, the chemical yield of @amino esters 17 and 18 decreased significantly (entry 4) but the diastereoselectivity did not change significantly. The addition of 23%HMPA14stopped the conjugate (14) Ireland, R. E.;Mueller, R. H.; Willard, A. K.J. Am. Chem. SOC.
+
1976, 98, 2868.
10142 J. Am. Chem. Soc.. Vol. 115, No. 22, 1993 Table
Suzuki et al.
II. Conjugate Addition of Organocoppers to 8 (Racemic)" yield, % diastereomer ratio (recovery of 8) 22:23
entry
8 (R)
R'CuLn
1
2 3
8a (Me) 8a (Me) 8e (Me)
PhCu-BFp Ph2CuLi.BF3 Ph2CuLisZBF3
29 (55) 79 73 (27)
4 5 6 7 8
8a (Me) 8a (Me) 8a (Me) 8c (Bu) 8c (Bu)
BuCu.BF3 Bu2CuLi.BF3 BuzCuLi.ZBF3 MeCu-BFj MezCuLi-ZBF3
68 55 73 23 (68) 70 (IO)
9 10 11 12 13
8c (Bu) 8c (Bu) 8d (Ph) 8d (Ph) 8d (Ph)
Ph2CuLi.BF3 PhzCuLi-ZBFo BUCWBF~ BuzCuLi-BF, BuzCuLi.2BF3
68 71 77 84 63
22x23~1 94:6 75:25 96:4 22b:23b
1000 89:ll 95:5 11:89 8:92 22€:23c 7225 90: 10 7:93 11:89 7:93
Normally, to an ether solution of 2 equiv of R'CuLn was added 1 equiv of 8 at -78 OC. The isomer ratio was determined by 'H N M R (entries 1-3, 9-13) or HPLC (entries 4-8).
addition completely. Perhaps HMPA prevents the chelation of lithium to the carbonyl oxygen because of its strong coordinating ability to lithium, and thus the yield diminishes to 30% by adding 13% HMPA. The uniform diasteroselectivity in the presence of HMPA clearly suggests that lithium does not operate to hold the orientation of two carbonyl groups in such as way as shown in 21; a strong conformational preference of the TMHD tether and two ester groups brings the ?r-electron systems close. Conjugate Additions of Organocopper Reagents. Since the addition of the nitrogen nucleophile proceeded with high diastereoselectivity, we next examined the conjugate addition of organocopper reagents to 8 (racemic). The results are summarized in Table 11. Very high diastereoselectivitywas accomplished
value with that of authentic (3R)-3-phenylbutyric acid, [a]25D -56.8O (c 9, C6H6),I6led to the assignment of the R configuration. Accordingly, the copper reagent attacks the double bond of the s-trans enoate from the front face (see 25). It is known that the conjugate addition of RCu in the presence of BF3.OEt2 proceeds via s-trans conformation,I6 and the present result is in good agreement with this previous conclusion. It should be noted that the conformation of enoate 8a dramatically changes from s-cis (9,Figure 1, and 20) to s-trans (25) in the presence of BF3.0Et2.17 Diels-Alder Reactions with Cyclopentadiene. To make clear the usefulness of the TMHD auxiliary, we next carried out DielsAlder reactions of racemic 8e with cyclopentadiene in CH2C12hexane at -78 OC. When a catalytic amount of Tic14 (0.5 equiv) was used, the diastereomer ratio of the endo adducts (26:27) was 91:9 and the chemical yield was 96%. The use of 1equiv of Tic14
A 27
26 1) 0 5 equiv TiCI,
2) 3) LIAIH,
h w
4
CHs\ J
v
I
23 a; R=Me. R1=Ph
b; R=Me, R'=Bu
b; R=Me. R'=Bu e; R=Bu. R1=Ph
E;
R=Bu. R'=Ph 1) Ph,CuLi*2BF3
w
8a (chiral)
2) KOH/H20-MeOH
24 [a]", -45.8'
(c 0.77, C6H6)
9KR
R'CuLn
H
-72.1" (c 0.332. BOH)
O
OCHzPh
tBY4&1BU Hb Hc
29 22 a; R=Me, R'=Ph
O
28
F!
R'
0
14 (chiral)
30
resulted in polymerization of cyclopentadiene, and the use of 0.1 equiv of Tic14 afforded an 87:13 mixture of 26 and 27 in 93% yield. The acrylate of @)-ethyl lactate reacts with cyclopentadiene in the presence of 0.5 equiv of Tic4 to afford a 92:8 mixture of the corresponding endo adducts along with small amounts of the exo adducts.18 Diphenylmethyl- and 3,3dimethylbutyl-shielded camphor auxiliaries, which have a conformationally rigid cyclictether, produce 6694%de in the DielsAlder reaction of the acrylates with cyclopentadiene.lc We next examined the addition of chiral 14 with cyclopentadiene to elucidate the face selection. The reduction of the adduct with LiAlH4 gave 28: [ c ~ ] -72.1O ~ ~ D (c 0.332, EtOH). Comparison of this [ a ] value ~ with that of the authentic R enantiomer (70% ~
25
s-trans
by using organocopper.BF3 reagents.I5 The use of TMSCl instead of BF.OEt2 resulted in low conversion and low diastereoselectivity.15 It should be noticed that the use of RzCuLi.2BF3.OEt2 enhanced the diastereoselectivityin comparison with the conjugate addition via R2CuLi.BF3.OEt2 (entry 3 vs 2, 6 vs 5, 10 vs 9, 13 vs 12), and chemical yields in some cases were also enhanced with this reagent. In order to determine the stereochemistry of 22 (major products in entries 1-6,9, and 10) and to elucidate the conformation of 8 in the transition state, the conjugate addition of phenylcopper reagent to chiral 8a was carried out. The conjugate adducts were treated with KOH in H20-MeOH to afford 24; [ ~ u ] ~ ~ ~ - 4(c 5 0.77, . 8 O C6H6). Comparison of this [ a ] ~ (15),(a) Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986,25,947. (b) Alexaks, A,; Besace, B. Tetrahedron Lett. 1986, 27, 1047.
~~~
(16) Oppolzer, W.; Loher, H. J. Helv. Chim. Acta 1981, 64, 2808.
(17) X-ray analyses of enoates and enamides were carried out. S-Trans conformations: (a) Oppolzer, W.; Chapuis,C.; Bernardinelli, G. Tetrahedron Lett. 1984, 25, 5885. (b) Oppolzer, W.; Kelly, M. J.; Bernardinelli, G. Tetrahedron Lett. 1984, 25, 5889. (c) Barnes, J. C.; Brimacombe, J. S.; Irvine,D.J. Carbohydr.Res. 1990,200,77. s-Cisconformations: (d) Oppolzcr, W.; Rodriguez, I.; Blagg, J.; Bernardinelli, G. Helu. Chim. Acta 1989, 72, 123. (e) Poll, T.; Metter, J. 0.;Helmchen, G. Angew. Chem., Inr. Ed. Engl. 1985,24,112. ( f ) Katagiri, NI; Watanabe, N.; Sakaki,J.; Kawai, T.; Kaneko, C. Tetrahedron Lett. 1990,31,4633. (8) Koizumi, T.; Arai, Y.;Takayama, H.; Kuriyama, K.; Shiro, M. Tetrahedron Lett. 1987, 28, 3689. (h) Wolff, S.;Venepalli, B. R.; George, C. F.; Agosta, W. C. J . Am. Chem. SOC.1988, 110, 6785. (i) Mara, A. M.; Singh, 0.;Thomas, E. J., Williams, D. J. J. Chem. Soc., Perkin Trans. I 1982, 2169. Wiedenfeld, H.; Kirfel, A.; Roder, E.; Will, G. Arch. Pharm. 1985, 318, 294. (k) Elliot, J. E.; Khalaf, M. M.; Jephcose, V. J.; John, D. I.; Williams, D. J.; Allwood, B. L. J. Chem. Soc., Chem. Commun. 1986, 584. (I) Reference 1Oc. (m) Bethell, D.; Chadwick, D. J.; Harding, M. M.; Maling, G.Q.;Wiley, M. D. Int. Union Crystallogr. 1985,470. s-Trans in the presence of SnC4. (n) Lewis, F. D.; Oxman, J. D.; Huffman, J. C. J . Am. Chem. SOC.1984, 106,466. (18) Pull, T.; Helmchen, G.; Bauer, B. Tetrahedron Lett 1984,25,2191.
u)
2,2,6,6-Tetramethyl-3,5-heptanediolDerivative ee), [ a I z 5+67.7O ~ (c = 0.718, EtOH),19 led to the assignment of the S configuration. Accordingly, cyclopentadiene attacks s-tram-acrylate from the re face of the olefin (29). As pointed out previously, the Lewis acid presumably is essential for stabilization of the acrylate s-trans conformation relative to its s-cis form.lCJo
Conclusion The rigid coplanar ?r-stacking structure of 8 (as shown in 9, 20,25,and 29)is due not merely to the presence of two tert-butyl groups but also to the presence of two ester groups. As is evident from the X-ray structure of 13 shown in Figure 2, the carbon chain of 13does not adopt a zigzag structure as in 9. The coupling constants of 13 also indicate a distorted framework; J,, = 7.0 Hz, Jab = 2.0 Hz, J d = 11.5 Hz, and JM = 1.8 Hz. The distorted structure of 30 is also confirmed by the coupling constants; J,, =2.5Hz,Jab=6.5Hz,J~=1.7Hz,andJd=: 11.0Hz. These results clearly indicate that when one of the two hydroxy oxygen substituents changes from a carbonyl to an alkyl group, perfect coplanarity of the two substituents at the C-3 and C-5 positions in 6is lost, resulting in decreased asymmetric induction. In fact, the conjugate addition of Bu2CuLb2BF3to 30 produced an 80:20 mixture of diastereomers. The ?r-stacking effect together with the perfect overlapping of the two ester planes is apparent from the coupling constants of 12;J,, = 9.0 Hz, Jab 2.5 Hz, JM = 3.5 Hz, and J d = 7.5 Hz. The double bond of the enoates is not a key factor for adopting a zigzag framework;rather, the presence of the two ester groups in addition to the tert-butyl groups is essential for producing high asymmetric induction in the above reactions. The chiral auxiliaries first developed by Evans, Oppolzer, and Helmchen for enolate alkylation, aldol reaction, and Diels-Alder cycloaddition were assigned to be chelating.' Concurrently, auxiliaries that depended only on conformational effects of cyclic systems were developed (Corey and Ens1ey:o Whitesell'). More recently, asymmetric inductions in which the conformationalrestraints of acyclic substituentsattached to cyclic templates dictate the reaction course have been reported.2' The newly developed TMHD auxiliary is not unique in achieving induction without chelation. It is novel that it is totally acyclic, yet allows a strong preference for the convergent conformation necessary for remote induction. Although further workis needed in order to extend the present acyclic template to an induced fit type chiral auxiliary, TMHDiol derivativeshave already provided a synthetically useful level of asymmetric induction, e.g. for the synthesis of @-aminoesters.
Experimental Section
5-Hydroxy-2,2,6,6,-tetramethyheptan-3-one. Diisopropylamine (16.8 mL, 0.12 mol) was dissolved in 100 mL of dry THF at 0 OC. To this solution was added dropwise a hexane solution of n-BuLi (1.16 M, 68.3 mL). The mixture was stirred for 10 min and then cooled to -78 OC. Pinacolone (12.5 mL, 0.1 mol) was added via a syringe, and stirring was continued for 20 min. To the resulting white suspension was added pivalaldehyde (10.9 mL, 0.1 mol) via a syringe. The mixture was stirred for 2 h at -78 OCand thenpouredintoanaqueoussaturatedNH4Clsolution. The usual workup gave 17.6 g of the &hydroxy ketone as a white solid (97%). Without further purification, the product was used (19) Oppolzer, W.; Kurth, M.; Reichlin, D.; Moffat, F. Tetrahedron Lett. 1981, 22, 2545. (20) Corey, E. J.; Ensley, H. E. J . Am. Chem. Soc. 1975, 97, 6909. (21) For example, see: (a) Tomioka, K.; Kawasaki, H.; Yasuda, K.; Koga, K. J . Am. Chem. SOC.1988,110,3597. (b) Suzuki, K.; Seebach, D. Liebigs Ann. Chem. 1992, 51. (c) Amberg, W.; Seebach, D. Chem. Ber. 1990,123, 2413. (d) Seebach, D.; Lamatsch, B.; Amstutz, R.; Beck, A. K.,; Dobler, M.; Egli, M.; Fitzi, R.; Gautschi, M.; Harradon, B.; Hidber, P. C.; Irwin, J. J.; Locher, R.; Maestro, M.; Maetzke, T.; Mourino, A.; Pfammatter,E.; Plattner, D. A.; Schickli, C.; Schweizer, W. B.; Seiler, P.; Stucky, G.; Petter, W.; Escalante, J.; Juaristi, E.; Quintana, D.; Miravitlles, C.; Molins, E. Helv. Chim. Acta 1992, 75, 913.
J. Am. Chem. SOC.,Vol. 115, No. 22, 1993
10143
as the starting material of the next transformation: 1H NMR (CDCl3) 6 3.66 (lH,ddd, J = 10.1,2.0, and 1.7 Hz), 3.17 (lH, d, J = 2.0 Hz), 2.72 (lH, dd, J = 17.1 and 1.7 Hz), 2.43 (lH, dd, J = 17.1 and 10.1 Hz), 1.16 (9H, s) 0.92 (9H, s); IR (KBr) 3475, 2800, 1700, 1460, 1380, 1360, 1320, 1280, 1060, 1000 cm-l. meso-2,2,6,6Tetramethyl-3,5-heptanediol(6) ( m o l ) . To a solution of 5-hydroxy-2,2,6,6-tetramethylheptan-3-one(4.66 g, 25 mmol) in THF (100 mL) was added Dibal(1 M in hexane, 55 mL, 55 mmol) at -78 OC, and the solution was stirred for 2 h at this temperature. The reaction mixture was allowed to warm to room temperature and quenchedwith 2 N aqueous HC1solution. The mixture was extracted twice with ether, and the combined organic layer was washed with saturated aqueous NaHCO3 solution and with brine. Drying with anhydrous MgSO4 and concentration gave 6 (4.56 g, 97% yield, syn:anti = 95:5) as a white solid: 'H NMR (CDCl3) 6 3.45 (2H, dd, J = 2.0 and 13.8 Hz), 2.78 (2H, bs), 1.73 (lH, ddd, J = 2.0, 2.0, and 19.0 Hz), 1.28 (lH, ddd, J = 13.8, 13.8, and 19.0 Hz), 0.91 (18H, s); IR (KBr) 3400, 2900, 1470, 1100, 880 cm-'. Anal. Calcd for CllH2402: C, 70.16; H, 12.85. Found: C, 70.10; H, 12.66. 5-(Benzoyloxy)-2,2,6,6,-tetramethylptan3-ol(7).To a suspension of KH (1.2 g, 35 wt %, 10.5 mmol) in 40 mL of dry THF was added under N2 a solution of TMHDiol (6)(1.97 g, 10.5 mmol) dissolved in 20 mL of dry THF. Stirring was continued for 30 min at room temperature, and a THF (7 mL) solution of benzoyl chloride (1.2 mL, 10.3 mmol) was added. The resulting mixture was stirred overnight and quenched with saturated aqueous NH4Cl solution. The usual workup gave 3.9 g of crude product. Purification with column chromatography (lOOg, SiOz, hexane:AcOEt = 50:l as an eluant) afforded 3.04 g of 7 (99% yield): lH NMR (CDCl3) 6 8.10-8.02 (2H, m), 7.62-7.40 (3H, m), 4.92 (lH, dd, J = 4.2 and 5.9 Hz), 3.38 (lH, dd, J = 1.5 and 10.0 Hz), 2.11 (lH, ddd, J = 15.5, 4.2, and 1.5 Hz), 1.48 (lH, ddd, J = 15.5, 10.0, and 5.9 Hz), 1.02 (9H, s), 0.90 (9H, s); IR (KBr) 3460, 2940, 2860, 1680, 1590, cm-l. Anal. Calcd for ClgH2gO3: C, 73.93; H, 9.65. Found: C, 73.86; H, 9.56. 3-(Benzoyloxy)-2,2,6,6tetramethyl-5-heptyl Crotonate (8a). To a solution of 7 (806 mg, 2.76 mmol) dissolved in dry benzene (10 mL) kept under N2 were added AgCN (402 mg, 3.0 mmol) and crotonyl chloride (0.30 mL, 3.0 mmol). The mixture was refluxed for 2 h and then cooled to room temperature. The resulting mixture was filtrated and dried over anhydrous MgS04. Removal of the solvent under reduced pressure and purification with column chromatography (60 g, SiO2, hexane:EtOAc = 30: 1 as an eluant) gave 857 mg of 8a (86%): 'H NMR (CDCl3) 6 8.04-7.96 (2H, m), 7.56-7.36 (3H, m), 6.58 (lH, dq, J = 15.8 and 6.8 Hz), 5.55 (lH, dq, J = 15.8 and 1.4 Hz), 5.06 (lH, dd, J = 2.5 and 8.5 Hz), 4.95 (lH, dd, J = 2.5 and 8.5 Hz), 2.07 (lH, ddd, J = 15.0, 2.5, and 2.5 Hz), 1.78 (lH, ddd, J = 15.0, and 8.5 Hz), 1.60 (3H, dd, J = 1.4 and 6.8 Hz), 0.98 (9H, s), 0.90 (9H, s); IR (KBr) 3090, 3060, 3030, 2960, 2870, 1720, 1665,1600, 1580, 1480, 1450cm-l. Anal. Calcd for C22H3204: C, 73.30; H, 8.95. Found: C, 73.13; H, 8.93. ~((Benz0yl0~y)-2,2,6,6,-tetramethyl-5-~~l2-Pe11te110ak (a). A procedure similar to that described for 8a was employed: 1H NMR (270 MHz, CDCl3) 6 8.40-7.96 (2H, m), 7.56-7.36 (3H, m), 6.66 (lH, dt, J = 15.0 and 6.0 Hz), 5.52 (lH, dt, J = 15.0 and 1.5 Hz), 5.08 (lH, dd, J = 8.0 and 2.5 Hz), 4.96 (lH, dd, J = 8.9 and 2.5 Hz), 2.08 (lH, ddd, J = 15.3, 2.5, and 2.5 Hz), 1.96 (2H, m), 1.79 (lH, ddd, J = 15.3, 8.9, and 8.0 Hz), 0.97 (9H, s), 0.91 (9H, s), 0.89 (3H, t, J = 7.3 Hz); IR (CC14)2950, 2875, 1710, 1650, 1360, 1340, 1265, 1170, 1105, 1040 cm-l. Anal. Calcd for C23H3404: C, 73.26; H, 9.22. Found: C, 73.48; H, 8.97. I(Beozoyloxr)-22,6,6,-tetramethyl-5-heptyl bHeptenoate (&). A procedure similar to that described for 8a was employed: lH NMR (CDC13) 6 8.04-7.96 (2H, m), 7.60-7.30 (3H, m), 6.63
10144 J. Am. Chem. SOC..Vo1. 115, No. 22, 1993 (lH, dq, J = 15.3 and 6.3 Hz), 5.53 (lH, dq, J = 15.3 and 1.5 Hz), 5.07 (lH, dd, J = 2.9 and 8.5 Hz), 4.95 (lH, dd, J = 2.5 and 9.0 Hz), 2.08 (lH, ddd, J = 2.5,2.9, and 15.1 Hz), 2.00-1.86 (2H, m), 1.78 (lH, ddd, J = 8.5, 9.0, and 15.1 Hz), 1.30-1.22 (2H, m), 1.0-0.80 (5H, m), 0.97 (9H, s), 0.91 (9H, s); IR (KBr) 2960, 2930, 2870, 1720, 1650, 1270, 1165, 1110 cm-I. Anal. Calcd for C2sH3804: C, 74.59; H, 9.51. Found: C, 74.64; H, 9.50. 3-(Benzoyloxy)-2,2,6,6-tetramethyl-5-heptyl Cinnamate (8d). A procedure similar to that described for 8a was employed: IH NMR(CDCl3)67,95(2H,m),7,28(1H,d,J= 15.8Hz),7.4& 7.20 (8H, m), 6.13 (lH, d, J = 15.8 Hz), 5.1 1 (lH, dd, J = 8.2
and2.5Hz),5.03(1H,dd,J=9.1and2.5Hz),2.11(1H,ddd, J = 15.0,2.5, and 2.5 Hz), 1.85 (lH, ddd, J = 15.0,9.1, and 8.2 Hz), 0.99 (9H, s), 0.94 (9H, s); IR (KBr) 3060, 2960, 2870, 1730, 1635, 1600, 1570, 1480, 1470, 1445, 1260, 1160 cm-I. Anal. Calcd for C27H3404: C, 76.75; H, 8.1 1. Found: C, 76.72; H, 8.11. 3-(Benzoyloxy)-2,2,6,6,-tetramethyl-5-heptyl Acrylate (8e). To a stirred solution of 7 (575 mg, 2.1 mmol) in 4 mL of CHZClz were added tributylamine (1.2 mL, 4.8 mmol) and acrylic acid (151 mg, 2.1 mmol). To this solution was added 2-chloro-lmethylpyridinium iodide (720 mg, 2.4 mmol). After refluxing for 2 h, removal of the solvent under reduced pressure and purification with column chromatography (40 g, SiOz, hexane: EtOAc = 20:l as an eluant) gave 535 mg of 8e (74%): IH NMR (270MHz,CDC13)68.0&7.35(5H,m),6.09(1H,dd,J= 17.5 and 1.5 Hz), 5.87 ( l H , d d , J = 17.5 and 10.5 Hz), 5.54 (lH,dd, J = 10.5 and 1.5 Hz), 5.06 (lH, dd, J = 8.4 and 3.5 Hz), 4.97 (lH,dd,J=8.8and2.7Hz),2.12(lH,ddd,J= 15.0,3.5,and 2.7 Hz), 1.78 (lH, ddd, J = 15.0, 8.8, and 8.4 Hz), 0.98 (9H, s), 0.91 (9H, s); IR (neat) 2950, 1720, 1470, 1400, 1360, 1280, 1180 cm-I. Anal. Calcd for C21H3004: C, 72.80; H, 8.73. Found: C, 72.45; H, 8.93. (3S,5R)-5-(a-Menthoxyacetoxy)-2,2,6,6tetramethylheptan3-01(10). To a suspension of KH (721 mg, 35 wt %) in dry THF (20 mL) was added under NZa solution of THMDiol (6)(1.14 g, 6 mmol) dissolvedindry THF (20 mL). Stirring wascontinued for 40 min at room temperature. A solution of a-methoxyacetyl chloride (1.43 g, 6.2 mmol) in dry THF (1 5 mL) was added. The reaction mixture was stirred overnight and then quenched with saturated aqueous NH4Cl solution. The usual workup followed by purification with column chromatography(100 g, SiOz, hexane: EtOAc = 30:l as an eluant) gave 1.73 g of 10 (76% yield) as an oil. Two diastereomers were separated by HPLC (D-SIL-546 of YMC, hexane:EtOAc = lO:l, flow = 5 mL/min, t~ = 25.4 and 28.163 min). (10') (3R,5S)-5-(a-Menthoxyacetoxy)-2,2,6,6 tetramethyIheptan-3-01(10') ( t =~25.4 min): IH NMR (CDC13) 6 4.81 (lH, dd, J = 4.5 and 7.5 Hz), 4.12 (2H, ABq, J = 16.0 Hz, Av = 16.0 Hz), 3.30 (lH, dd, J = 9.5 and 1.OHz), 3.16 (1H, ddd, J = 10.0, 10.0, and 3.9 Hz), 2.29 (lH, m), 2.12-2.0 (lH, m), 2.0-1.9 (lH, m), 1.70-1.58 (2H, m), 1.46-1.22 (4H, m), 1.72 (lH, bs), 0.92 (9H, s), 0.90 (3H, d, J =6.5 Hz), 0.89 (3H, d, J = 6.5 Hz), 0.79 (3H, d, J = 6.5 Hz), 0.96-0.85 (2H, m); IR (neat) 3500,2950,2870,1760,1480,1460,1370,1270,1200, 1100 cm-I. Anal. Calcd for C23H4404: C, 71.83; H, 11.53. Found: C, 72.00; H, 11.68. 10 (ZR = 28.163 min): IH NMR (CDC13) 6 4.81 (IH, dd, J = 7.5 and 4.5 Hz), 4.12 (2H, ABq, J = 15.5 Hz, Av = 27.0 Hz), 3.30 (lH, bd, J = 9.5 Hz), 3.15 (lH, ddd, J = 10.5, 10.5, and 3.7 Hz), 2.30 (lH, m), 2.06 (lH, m), 1.94 (lH, m), 1.70-1.56 (2H, m), 1.461.42 (4H, m), 0.92 (9H,s),0.87(9H,s),0.89(6H,d,J=6.0Hz),0.78(3H,d,J-6.5 Hz), 0.954.85 (2H, m); IR (neat) 3500,2950,2870,1760,1480, 1460, 1365, 1270, 1200, 112Ocm-I. Anal. Calcd for C23H4404: C, 71.83; H, 11.53. Found: C, 71.90; H, 11.50. (3R,SS)-5-[(Beazyloxy)methoxy]-3-(a-menthoxyacetoxy)2,2,6,6-tetramethylheptane(11). To a solution of the alcohol 10 (751 mg, 1.95 mmol) in CHzClz (8 mL) were added 0.85 mL of
Suzuki et al. diisopropylethylamine (4.9 mmol) and 0.54 mL of benzyl chloromethyl ether (3.9 mmol). The mixture was refluxed for 2 h and then cooled to room temperature. Ether was added, and the organic layer was washed twice with aqueous 1N HCl solution, twice with saturated aqueous NaHCO3 solution, and with brine. The usual workup and purification with column chromatography (SiO2, 40 g, hexane:EtOAc = 50:l as an eluant) gave 957 mg of 11 as a colorless oil (97% yield): *HNMR (CDCl3) 6 7.407.20 (5H, m), 4.85 (lH, dd, J = 12.0 and 1.9 Hz). 4.71 (2H, ABq, J = 6.9 Hz, Av = 44 Hz), 4.61 (2H, ABq, J = 11.8 Hz, Av = 21.0 Hz), 4.08 (2H, ABq, J = 16.2 Hz, Av = 16.2 Hz), 3.20 ( l H , d d , J = 7.0and 1.5 Hz), 3.04 (lH,ddd,J= 10.5, 10.5, and 4.0Hz),2.31 (lH,m),2.06(1H,ddd,J= 15.0,7.0,and1.9Hz), 1.96 (lH, m), 0.95 (9H, s), 0.91 (9H, s), 0.87 (3H, d, J = 6.5 Hz), 0.86 (3H, d, J = 6.5 Hz), 0.74 (3H, d, J = 6.9 Hz), 1.800.90 (IOH, m); IR (neat) 2960, 2875, 1750, 1720, 1450, 1360, 1280, 1120, 1040, 1020 cm-I. Anal. Calcd for C3lH5205: C, 73.77;H, 10.38. Found: C,73.76;H, 10.12. Thesameprocedure as above was used for the synthesis of 11' from 10': lH NMR (CDC13) 6 7.40-7.20 (5H, m), 4.84 (lH, dd, J = 11.7 and 1.9 Hz), 4.71 (2H, ABq, J = 7.5 Hz, Av = 45.0 Hz), 4.61 (2H, ABq, J = 12.0 Hz, Av = 28.0 Hz), 4.08 (2H, ABq, J = 16.0 Hz, Av = 61.0 Hz), 3.20 (lH, dd, J = 6.9 and 1.5 Hz), 3.01 (lH, ddd, J = 10.5, 10.5,4.2 Hz), 2.27 (lH, m), 2.05 (lH, ddd, J = 15.2, 6.9, and 1.9 Hz), 1.96 (lH, m), 0.95 (9H, s), 0.91 (9H, s), 0.88 (3H, d, J = 6.5 Hz), 0.87 (3H, d, J = 6.5 Hz), 0.74 (3H, d, J = 6.8 Hz), 1.70480 (lOH, m); IR (neat) 2960, 2875, 1750, 1720, 1450, 1360, 1280, 1120, 1050, 1020 cm-*. Anal. Calcd for C3lHs20s: C, 73.77; H, 10.38. Found: C, 73.76; H, 10.29.
(3R,5s)-5-{(Benzyloxy)methoxy)l-2,2,6,6,-tetramethylheptan3-01(11-1). To a solution of 11 (957 mg, 1.89 mmol) in 90% MeOH-HZO (10 mL) was added KOH (1.134 g, 20 mmol). The mixture was refluxed for 2 h and then diluted with ether. The organic layer was washed twice with brine, dried with anhydrous MgS04, and concentrated under reduced pressure. Purification of the crude product with column chromatography (40 g of Merck SiOz, hexane:AcOEt = 30:l as an eluant) gave 570 mg of the desired product (95% yield): IH NMR (CDCl3) 6 7.40-7.25 (5H, m), 4.89 (2H, ABq, J = 6.5 Hz, Av = 20.5 Hz), 4.68 (2H, ABq, J = 12.0 Hz, Av = 21.0 Hz), 3.38 (lH, dd, J = 6.5 and 4.0 Hz), 3.30 (lH, dd, J = 10.2 and 1.8 Hz), 1.90 (lH, ddd, J = 15.0,4.0, and 1.8 Hz), 1.41 (lH, ddd, J = 15.0, 10.2, and 6.5 Hz), 0.91 (9H, s), 0.88 (9H, s), 0.88 (9H, s); IR (neat) 3500, 2975, 2880, 1480, 1390, 1360, 1160, 1040, 1020 cm-I. (3R,SS)-3-(Benzoyloxy)-5-{(benzyloxy)methoxy)]-2,2,6,6tetramethylbeptane (11-2). To a solution of the alcohol 11-1 (421 mg, 1.36 mmol) in pyridine (4 mL) was added at room temperature 0.32 mL of benzoyl chloride (2.7 mmol). Stirring was continued overnight. The usual workup gave 750 mg of yellow oil. Purification with column chromatography(50 g, SiOz, hexane:EtOAc = 50:l as an eluant) afforded 544 mg of 11-2 (97% yield): 'H NMR (CDCl3) 6 8.00-7.93 (2H, m), 7.50-7.40 (IH, m), 7.367.26 (2H, m), 7.20-7.10 (3H, m), 7.02-6.96 (2H, m), 4.95 (2H, dd, J = 1.9 and 11.0 Hz), 4.60 (2H, ABq, J = 6.5 Hz, Av = 43.3 Hz), 4.40 (2H, ABq, J = 12.1 Hz, Av = 33.4 Hz), 3.22 (lH, dd, J = 7.0 and 1.9 Hz), 2.09 (lH, ddd, J = 15.6,7.0, and 1.9 Hz), 1.68 (lH, ddd, J = 15.6, 11.0, and 1.9 Hz), 0.92 (9H, s), 0.91 (9H, s); IR (KBr) 2950, 2890, 2870, 1700, 1595, 1560, 1470, 1445, 1360, 1270, 1155, 1100, 1050, 1040 cm-l. Anal. Calcd for C26H3604: C, 75.69; H, 8.80. Found: C, 75.74; h, 8.71. (3S,5R)-5-(Benzoyloxy)-2,2,6,6-tetramethylbeptan-3-ol [(7 (Chiral)]. To a solution of the BOM ether 11-2 (718 mg, 1.74 mmol) in 4 mL of EtOH was added 72 mg of Pd(OH)2. Hydrogen was introduced into the flask, and the mixture was stirred overnight at room temperature. Purification of the crude product with
2.2.6,6- Tetramethyl-3,5-heptanediolDerivative column chromatography (20 g of SiO2; hexane:AcOEt = 30:l as an eluant) gave 493 mg of 7 (chiral) as a colorless oil (97% yield): [.Iz3D 30.27 (C 0.094, csH.5). 7' (chiral): [(Ylz3D-30.42(C 0.093, C6Hd (3R,5S)-3-( Benzoyloxy)-5-(butanoyloxy)-2,2,6,6-tetramethylheptane (12). To a solution of 7 (chiral) (445 mg, 1.52 mmol) dissolved in 6 mL of CH2C12 were added at 0 OC pyridine (0.5 mL) and butyryl chloride (0.24 mL, 2.3 mmol). Stirring was continuedovernight at room temperature. The usual workup and purification with column chromatography(50 g Si02, hexane: EtOAc = 50:l as an eluant) gave 470 mg of 12 (85% yield) as a colorless oil: IH NMR (CDCl3) 6 8.10-8.00 (2H, m), 7.607.30 (3H, m), 5.02 (lH, dd, J = 7.5 and 3.5 Hz), 4.91 (lH, dd, J = 9.0 and 2.5 Hz), 2.09 (IH, ddd, J = 15.2, 3.5, and 2.5 Hz), 2.07 (2H, t, J = 7.2 Hz), 1.71 (lH, ddd, J = 15.2, 9.0, and 7.5 Hz), 1.55-1.30 (2H, m), 0.98 (9H, s), 0.89 (9H, s), 0.81 (3H, t, J = 7.5 Hz); IR (neat) 2960, 2870, 1760, 1730, 1560, 1270, 1170 cm-l. Anal. Calcd for C22H3404: C, 72.89; H, 9.45. Found: C, 72.99; H, 9.54.
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J. Am. Chem. Soc., Vol. 115, No. 22, 1993 10145
= 6.0 Hz), 2.11 (lH, ddd, J = 15.2, 3.8, and 2.5 Hz), 1.70 (lH, ddd, J = 15.2, 8.8, and 7.5 Hz), 1.50-1.30 (2H, m), 0.98 (9H, s), 0.89 (9H, s), 0.81 (3H, t, J = 7.2 Hz); IR (neat) 3350, 2980, 2880, 1720, 1450, 1360, 1270, 1160 cm-I. Anal. Calcd for C30H43NO4: C, 74.81; H, 9.00; N, 2.91. Found: C, 74.43; H, 8.97; N, 2.95. 2.5 Hz), 3.66 (2H, s), 2.77 (lH, m), 2.27 (2H, d, J
(3S+,SR*)-5-(Benzoyloxy)-2,2,6,6tet~amethyl-3-beptyl(3S+)3-(Benzylamino)hydrocinnamate (17c). A procedure similar to that described for 17a was employed: IH NMR (270 MHz, CDCl3) d 8.02-7.98 (2H, m), 7.53-7.18 (13H, m), 5.01 (IH,dd, J = 7.5 and 3.5 Hz), 4.91 (lH, dd, J = 9.0 and 2.5 Hz), 3.99 (IH, dd, J = 9.5 and 4.0 Hz), 3.48 (2H, ABq, J = 12.5 Hz, Au = 13.0 Hz), 2.55 (lH, dd, J = 16.5 and 9.5 Hz), 2.43 (lH, dd, J = 16.5 and 4.0 Hz), 2.08 (lH, ddd, J = 15.5,3.5, and 2.5 Hz), 1.66 (lH, ddd, J = 15.5,9.0, and 7.5 Hz), 0.97 (9H, s), 0.85 (9H, s); IR (neat) 3350, 2950, 2980, 1720, 1450, 1370, 1280, 1160 cm-I. Anal. Calcd for C34H43N04: C, 77.09; H, 8.18; N, 2.64. Found: C, 76.68; H, 7.89; N, 2.49. (3R,5S)-3-(Benzoyloxy)-2,2,6,6tetramethyl-5-heptyl CrotoConjugateAddition to 8. The addition of Bu2CuLi.2BF3 to 8a nate[8a (Chiral)]. To a THF (4 mL) solution of diisopropylamine is representative. In a 30-mL two-necked flask, equipped with a magnetic stirrer and maintained under Ar, were placed 95.6 (0.21 mL, 1.5 mmol), cooled at 0 OC, was added BuLi-hexane mg (0.50 mmol) of CUIand 4 mL of dry ether. BuLi in hexane solution (0.74 mL X 1.62 M, 1.2 mmol). The mixture was stirred for 10 min and then cooled to -78 OC. A THF (4 mL) solution (1.64 M, 1 mmol) was added at -55 OC, and the resulting mixture of the ester 12 (370 mg, 1.0 mmol) was added. The reaction was stirred for 20 min at this temperature. The mixture was mixturewasstirred for 10minat-78 OC. To thereactionmixture cooled to -78 OC, and 0.13 mL (1.0 mmol) of BF3-OEt2 was was added 350 mg of PhSeSePh (1.1 mmol) in THF (4 mL). The added. The mixture was stirred for a while, and then an ether (3 mL) solution of 84.7 mg (0.23 mmol) of 8awas added. Stirring resulting mixture was allowed to warm to room temperature and was continued for 1 h below -50 OC. The reaction was quenched quenched with a saturated aqueous solution of NH4Cl. The aqueous layer was extracted twice with ether, and the combined with saturated aqueous NHlCl solution and extracted three times organic phase was washed with brine and dried over MgS04. The with ether. The combined organic layer was dried over anhydrous solvent was removed under reduced pressure, and 550 mgof crude MgS04. Removal of the solvent under reduced pressure gave product was obtained. This crude product was used for further 108 mg of crude product. Purification with column chromapurification. To the crude product dissolved in 3 mL of AcOEttography (10 g, 2302, hexane:EtOAc = 50.1 as an eluant) afforded THF (2:l) at 0 OC were added 250 mg of NaHCO3 and 0.4 mL 71.7 mg (74% yield) of the conjugate adducts as an oil. The of 30% H202. The mixture was stirred overnight at room diastereoisomer ratio was determined by HPLC (YMCRtemperature. The resulting mixture was diluted with ether and SIL-5-06); 22b (tR = 22.43 min):23b ( t =~ 23.35 min) = 955. washed twice with a saturated aqueous solution of Na2S203 and (3~,59)-5-(Benzoyloxy)-2,2,6,6tetrametl1yl-3-~ptyl(3S*)of NaHCO3 and with brine. The usual workup and purification 3-methylheptanoate (22b): 'H NMR (CDCl3) 6 8.10-8.0 (2H, with silica gel column chromatography(Si02,30 g, hexane:AcOEt m), 7.60-7.36 (3H, m), 5.20 (lH, dd, J = 7.4and 3.8 Hz), 4.90 = 30:l) gave 349 mg of the desired product (95%). (1 H, dd, J = 8.4 and 3.0 Hz), 2.10 (1 H, ddd, J = 14.9,3.8, and 3.0 Hz), 2.10 (1 H, dd, J = 15.2 and 5.5 Hz), 1.89 (1 H, dd, J (39,5R*)-5-( Benzoyloxy)-2,2,6,6-tetramethyl-3heptyl(39)3-(Benzylamino)butanoate (17a). To a solution of N-(tri= 15.2 and 8.5 Hz), 1.68 (1 H, ddd, J = 14.9, 8.4, and 7.4 Hz), 0.98 (9H, s), 0.90 (9H, s), 0.81 (3H, d, J = 6.5 Hz), 1.40-0.80 methylsily1)benzylamine (0.1 mL, 0.5 mmol) in THF (5 mL) at (lOH, m); IR (neat) 3060,3030,2960,2880, 1720, 1580,1465, 0 OC was slowly added n-BuLi (0.27 mL, 1.56 M in hexane, 0.42 1395, 1365, 1275, 1240, 1190, 1160, 1130, 1050, 1000 cm-l. mmol). After stirring for 20 min, the solution was cooled to -78 Anal. Calcd for C26H4204: C, 74.60; H, 10.1 1. Found: C, 74.56; OC. To this solution was added a solution of TMHD crotonate H, 10.17. 'H NMR (CDC13) of a minor isomer, 23b: 8.10-8.00 8a (169 mg, 0.41 mmol) in THF (3 mL). After stirring for an additional 10min, the reaction was quenched with 2 mLof MeOH. (2H,m),7.60-7.36(3H,m),5.02(1H,dd,J=7.2and3.9Hz), An aqueous saturated solution of NaHCO3 was added to the 4.89(1H,dd,J=8.9and3.0Hz),2.12(1H,dd,J= 15.1 and solution,and the mixture wasextracted twice with ether. Removal 6.0 Hz), 2.12 (lH, ddd, J = 15.0, 3.9, and 3.0 Hz), 1.93 (lH, of the solvent under reduced pressure and purification with column dd, J = 15.1 and 7.5 Hz), 1.69 (lH, ddd, J = 15.0, 8.9, and 7.2 chromatography (15 g, SiOz, hexane:EtOAc = 5:l as an eluant) Hz), 0.98 (9H, s), 0.91 (9H, s), 0.82 (3H, d, J = 6.7 Hz), 1.40gave 135 mg of 17a (96%). The diastereoisomer ratio was 0.80 (9H, m). determined by IH NMR: IH NMR (270 MHz, CDCl3) 6 8.60(39,SP)-5-(Be~yl0xy)-2,2,6,Ctetramethyl-3-beptyl(3R*)8.10(2H,m),7.58-7.36(3H,m),7.32-7.22(5H,m),5.02(1H,3-phenylbutanoate(22a): IH NMR (CDC13) 6 8.04-7.98 (2H, dd, J = 7.3 and 3.5 Hz), 4.91 (1H, dd, J = 9.0 and 2.8 Hz), 3.67 m), 7.604.98 (8H, m), 4.98 (lH, dd, J = 7.5 and 3.7 Hz), 4.87 (2H,ABq,J= 12.8Hz,Av=21.0Hz),2.91 (lH,m),2.31 (lH, (lH, dd, J = 8.8 and 2.9 Hz), 3.07 (lH, qdd, J = 6.7, 8.8, and d d , J = 1 6 . 0 a n d 7 . 2 H z ) , 2 . 1 8 ( 1 H , d d , J = 16.0and5.0Hz), 6.0 Hz), 2.52 (lH, dd, J = 16.0 and 6.0 Hz), 2.37 (lH, dd, J = 2.10 (lH, ddd, J = 15.0, 3.5, and 2.8 Hz), 1.71 (lH, ddd, J = 16.0 and 8.8 Hz), 2.07 (lH, ddd, J = 15.5,3.7, and 2.9 Hz),1.63 15.0, 9.0, and 7.3 Hz), 0.99 (3H, d, J = 6.5 Hz), 0.98 (9H, s), ( l H , d d d , J = 15.5,8.8,and7.5Hz), 1.16(3H,d,J=6.7Hz), 0.88 (9H, s); IR (neat). Anal. Calcd for C29H41N04: C, 74.48; 0.96 (9H, s), 0.83 (9H, s); IR (neat) 2960, 2870, 1720, 1600, H, 8.84; N, 3.00. Found: C, 74.25; H, 8.67; N, 3.00. 1580,1470,1450,1365,1270,1160,1110,1050,1020,990cm-1. (39,5R*)-5-(Benzoyloxy)-2,2,6,6tet~amethyl-3-heptyl(39)- Anal. Calcd for C28H3804: C, 76.68; H, 8.73. Found: C, 76.80; 3-(Beazylamino)pentanoate (17b). A procedure similar to that H, 8.76. A minor isomer, 23a,could not be isolated in a pure described for 17a was employed: IH NMR (270 MHz, CDC13) form, but was obtained as a mixture with 22a and identified by S 8.80-8.00 (2H, m), 7.57-7.37 (3H, m), 7.32-7.20 (5H, m), the lH NMR spectrum: IH NMR (CDC13) 6 8.08-7.98 (2H, 5.02 (lH, dd, J = 7.5 and 3.8 Hz), 4.92 (lH, dd, J = 8.8 and m), 7.60498 (8H, m), 4.98 (lH, dd, J = 7.5 and 3.7 Hz), 4.82
10146 J. Am. Chem. SOC..Vol. 115, No. 22, 1993
Suzuki et al.
(lH, dd, J = 8.9 and 2.5 Hz), 3.07 (lH, qdd, J = 7.5, 7.5, and 6.7Hz),2.47(1H,dd,J= 15.5and7.5Hz),2.37(1H,dd,J= 15.5 and 7.5 Hz), 2.07 (lH, ddd, J = 15.5,8.9, and 7.5 Hz), 1.62 (lH, ddd, J = 15.5, 3.7 and 2.5 Hz), 1.18 (3H, d, J = 6.7 Hz), 0.97 (9H, s), 0.74 (9H, s).
EtOAc = 50:l as an eluant) gave 135 mg of a desired product (96%). The diastereoisomer ratio was determined by HPLC (YMC R-SIL-5-06; hexane:AcOEt = 20:1, flow rate = 0.5 mL/ min) .
m), 7.60-7.96 (8H, m), 4.97 (lH, dd, J = 7.5 and 3.9 Hz), 4.76 (lH, dd, J = 8.9 and 2.9 Hz), 2.90 (lH, m), 2.45 (lH, dd, J = 15.5 and 6.5 Hz), 2.38 (lH, dd, J = 15.5 and 8.5 Hz), 2.03 (lH, d d d , J = 15.6,3.9,and2.9Hz), 1.8-0.8(10H,m),0.95(9H,s), 0.67 (9H, s); IR (neat) 2950, 2860, 1740, 1600, 1560, 1450, 1370,1260, 1160 cm-l. Anal. Calcd. for 31H~04:C, 77.46; H, 9.23. Found: C, 77.40 H, 9.33. A minor isomer, 23c could not be isolated in a pure form, but was obtained as a mixture with 22c: lH NMR (CDCl3) 6 8.07-7.97 (2H, m), 7.60-7.06 (8H, m), 4.95 (lH, dd, J = 7.9 and 3.8 Hz), 4.83 (lH, dd, J = 8.7 and 3.1 Hz), 2.89 (lH, m), 2.52-2.38 (2H, m), 2.04 (lH, ddd, J = 15.1, 3.8, and 3.1 Hz), 1.8-0.8 (lOH, m), 0.94 (9H, s), 0.76 (9H, SI. Diels-Alder Reaction between TMHD Acrylate and Cyclopentadiene in the Presence of 0.5 equiv of TiQ. To a stirred solution of TMHD acrylate (1 19 mg, 0.34 mmol) in 4 mL of CHzCl~hexane(1:l) was added Tic14 (0.17 mL, 1 M in CH2Cl2, 0.17 mmol) at -78 O C . After stirring for 10 min at this temperature, a solution of cyclopentadiene (0.5 mL) in CH2C12 was added to this yellow solution. The reaction mixture was allowed to warm to -30 OC and was stirred overnight at this temperature. The reaction was quenched with an aqueous saturated solution of NaHCOs, and the mixture was extracted twice with ether. The organic phase was washed with brine and dried over MgS04. Removal of the solvent under reduced pressure and purification with column chromatography( 10g, Si02, hexane:
7.35 (3H, m), 6.12 (lH, dd, J = 5.5 and 3.5 Hz), 5.78 (lH, dd, J = 5.8 and 2.9 Hz), 5.00 (lH, dd, J = 7.5 and 3.5 Hz), 4.83
(3R*,5S*)-3-(Benzoyloxy)-2,2,6,6-tetramethyl-5(3SL~~)-5-(Beazoyloxy)-2,2,6,6tetramethyl-3.heptyl(3R*)- heptyl(lsC,2s*,4R*)-5-norborwne-2carbo~la~ (26) ( f R = 19.8 3-phenylbeptanoate (22c): lH NMR (CDCl3) 6 8.08-7.98 (2H, min): 'H NMR 270 MHz, CDCls) 6 8.08-8.00(2H, m), 7.60-
(lH,dd,J=9.0and2.5Hz),3.03(1H,m),2.77(lH,m),2.74 (lH, ddd, J = 9.0, 3.5, and 3.5 Hz), 2.09 (lH, ddd, J = 15.5, 3.5,and2.5Hz), 1.71 ( l H , d d d , J = 15.5,9.0,and7.5Hz), 1.56 (lH, ddd, J = 11.5, 9.0, and 3.5 Hz), 1.31 (lH, ddd, J = 8.0, 4.5, and 1.5 Hz), 1.19 (lH, ddd, J = 1 1.5,4.5, and 2.5 Hz), 1.1 1 (lH, bd, J 8.0 Hz), 0.97 (9H, s), 0.91 (9H, s); IR (CCL) 2950, 2860, 1720, 1360, 1265, 1160, 1105 cm-l. Anal. Calcd for C26H3604: C, 75.69; H, 8.80. Found: C, 75.33; H, 9.05. (3R*,SS*)-3-(Benzoyloxy)-2,2,6,6-tetramethyl-5heptyl(lR*,2R*,49)-5-norbomene-2-carboxylate(27) ( f R = 21.6 min): 'H NMR (270 MHz, CDCls) 6 8.09-8.02 (2H, m), 7.597.39 (3H,m), 6.03 (lH, d d , J = 5.5 and 3.0Hz), 5.98 (lH, dd, J = 5.5 and 2.5 Hz), 5.00 (lH, dd, J = 7.5 and 4.0 Hz), 4.82 (lH, dd, J = 8.5 and 3.0 Hz), 3.05 (lH, m), 2.80 (lH, ddd, J = 9.5.4.0, and 3.0 Hz), 1.80-1.58 (2H, m), 1.38-1.08 (3H, m), 0.98 (9H, s), 0.85 (9H, s).
Acknowledgment. We thankDr. Chizuko Kabutofor theX-ray crystallographic analysis. Supplementary Material Available: Listing of crystal data, positional parameters, bond distances, and bond angles for 8d and 13 (19 pages). Ordering information is given on any current masthead page.
